Cell membranes are fundamental to life, and defects in their function underlie many diseases. Membranes of different organelles have different lipid compositions. For example, cholesterol is markedly enriched in the plasma membrane compared with the ER. Scientists know the enzymes that synthesize and degrade the various lipids in different cell membranes. Yet, very little is known about how these enzymes are regulated so as to maintain differential lipid compositions. Our laboratory made the initial inroad into this problem through the discovery of the SREBP family of transcription factors that control synthesis and uptake of cholesterol and fatty acids. We discovered four proteins whose actions govern the regulated trafficking mechanism that dictates the activities of SREBPs. We are now in a unique position to decipher precisely how this system works at a molecular level.